Five-year survival after invasive breast cancer is now at 90% and an estimated 2.97 million U.S. women are breast cancer survivors. The high incidence of invasive breast cancer, with over 220,000 U.S. women newly diagnosed every year, coupled with continued advances in survival has resulted in an ever- increasing number of women at risk of developing a second primary cancer. Indeed, 41% of all second primary cancers diagnosed among U.S. women occur among breast cancer survivors. Approximately 10% of breast cancer survivors will develop a second primary cancer. The four most common sites of second primary cancer, breast, lung, colon and endometrium, account for 70% of these second primaries. The appreciable risk of second primary cancer in breast cancer survivors is well-documented, yet relatively little is known about the etiologic and molecular determinants of these second primaries and little to no information on second primary cancer risk has been incorporated into preventive efforts and clinical care because of this evidence gap. No studies have comprehensively and simultaneously investigated the etiology of the four major second primary cancers diagnosed in breast cancer survivors. Dissecting relationships between therapies and risk of these second cancers, clarifying contributions of patient/clinical factors including modifiable exposures, and molecular profiling first primary breast tumors so as to distinguish those at highest and lowest risk of second primaries would potentially allow advances in risk stratification, tailored surveillance, treatment choice, preventive interventions, and understanding of biologic mechanisms. To address this gap we propose a population-based case-cohort study consisting of 2 600 breast cancer survivors focused on epidemiologic, clinical and molecular determinants of the four most common second primary cancers diagnosed after a first diagnosis of invasive breast cancer. Comparing women who have and have not developed second primary cancers, our primary specific aims are as follows: 1. To assess associations between epidemiologic/medical factors (including lifestyle factors; medications use for common medical conditions; family history of cancer) and risk of subsequent primary cancer of the breast, lung, colon and endometrium. 2. To assess associations between treatments for first primary breast cancer and risk of subsequent primary cancer of the breast, lung, colon and endometrium. 3. To assess associations between routinely collected clinical tumor characteristics of the first primary cancer (histology, tumor size, nodal status, grade, ER status, PR status, and HER2 status) and risk of subsequent primary cancer of the breast, lung, colon and endometrium. 4. To discover and preliminarily validate novel tumor biomarkers associated with risk of subsequent primary cancer of the breast, lung, colon and endometrium using a genome-wide gene expression platform.